Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/69—Two or more oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/61—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals

Definitions

• the present invention relates to a process for the preparation of 6-acetyl-3-amino-2,4-dihalogenopyridines and intermediates for their preparation.
• 6-Acetyl-3-amino-2,4-dihalogenopyridines have been disclosed from (DE-OS (German Published Specification) No. 3,615,293). They are prepared according to the process described there by hydrolysis and decarboxylation of the corresponding pyridylcarbonylacetic acid esters. These are obtained from the corresponding pyridylcarboxylic acid alkyl esters or acid chlorides by reaction with acetic acid esters and a suitable base. The pyridylcarboxylic acid alkyl esters or acid chlorides are prepared from the corresponding pyridylcarboxylic acids.
• the pyridylcarboxylic acids are obtained by oxidation of the 6-methyl-3-amino-2,4-dihalogenopyridine.
• 6-Methyl-3-amino-2,4-dihalogenopyridines are known. In this sequence of reactions it has still not been considered that, for example, an amino substituent of the pyridyl ring must be protected by acetylation before carrying out the reaction on another substituent.
• the present invention relates to:
• R 1 and R 2 stand for halogen, characterized in that 6-ethyl-3-amino-2,4-dihalogenopyridine of the formula II ##STR3##
• R 1 and R 2 have the abovementioned meaning, is first reacted with acylating agents, the compound of the formula II acylated on the amino group is subsequently oxidized using potassium permanganate in a medium maintained at a pH between 4 and 10 and the acyl radical of the amino group is then removed.
• R 1 and R 2 stand for halogen.
• R 1 and R 2 stand for halogen, characterized in that 6-ethyl-3-nitro-2,4-dihalogeno-pyridines of the formula III ##STR6##
• R 1 and R 2 have the abovementioned meaning are reduced.
• R 1 and R 2 stand for halogen.
• R 3 stands for OH or C 1-3 -alkoxy, are decarboxylated in the presence of bases.
• R 1 , R 2 and R 4 independently of one another stand for halogen
• 6-acetyl-3-amino-2,4-dihalo-genopyridines of the formula I are halogenated.
• 6-halogenacetyl-3-amino-2,4-dihalogenopyridines can be converted by reduction of the carbonyl group and subsequent reaction with primary or secondary amines into the corresponding 3-amino-2,4-dihalogeno-pyridylethanolamines. These are used as growth promoters in animals (DE-OS (German Published Specification) 3,615,293). supra.
• compounds of the formula I in which R 1 and R 2 stand for chlorine or bromine, are prepared by process 1.
• the acylation of the tirst step takes place using acetic anhydride, acetyl chloride or ketene.
• the reaction is preferably carried out in the presence of diluents. Those which may be mentioned are all inert organic solvents.
• these include aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, furthermore ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, in addition esters such as methyl acetate and ethyl acetate, furthermore nitriles such as, for example, acetonitrile and propionitrile,
• the acylation of the first step preferably takes place in the presence of basic catalysts or acylating catalysts.
• basic catalysts or acylating catalysts Those which may be mentioned are: for example tertiary amines such as pyridine, 4-dimethylaminopyridine, triethylamine, triethylenediamine, trimethylene-tetrahydropyrimidine; furthermore tin(II) and tin(IV) compounds such as tin(II) octoate or tin(IV) chloride.
• reaction accelerators such as, for example, pyridine, can also be used as solvents.
• Sodium acetate is particularly preferred.
• the reaction is carried out at 0°-250°C., preferably at 50°-150°C. It is carried out at atmospheric pressure.
• reaction mixture After completion of the reaction, the reaction mixture is diluted with water and extracted using a water-immiscible solvent. The extracting agent is removed by distillation. A mixture of the mono- or diacetylated compounds of the formula II are thus obtained. This mixture can either be further employed directly or can first be converted into the corresponding monoacetyl compounds by treating with bases in the presence of diluents.
• the conversion into the monoacetyl compound takes place in the presence of water, alcohols such as methanol, ethanol, i-propanol, acetone and mixtures thereof.
• Bases used are: hydroxides and carbonates of alkali metals and alkaline earth metals, and tertiary amines such as triethanolamine and 4-dimethylaminopyridine.
• the reaction is carried out at 0°-150°C., preferably at 10°-100°C. and atmospheric pressure. Water is added to the reaction mixture, it is extracted using a non-polar solvent and the solvent is removed by distillation. The residue is processed further in the second step.
• the acetylated compound of the formula II is oxidized using potassium permanganate at a pH of 4-10.
• the oxidation is carried out in water or mixtures of water with water-miscible organic diluents such as acetone, t-butanol, pyridine, acetonitrile and glycol dimethyl ether.
• water-miscible organic diluents such as acetone, t-butanol, pyridine, acetonitrile and glycol dimethyl ether.
• the pH of the solution is adjusted to 4-10, preferably 5-8, by means of buffer substances.
• Buffer substances used are alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate, magnesium nitrate or the mixture from magnesium oxide and nitric acid, magnesium sulphate, calcium sulphate, alkali metal bicarbonates and alkaline earth metal bicarbonates.
• the reaction can also be kept in the desired pH range by continuous addition of acids such as, for example, acetic acid.
• the oxidation is carried out at temperatures of 0° to 70°C., preferably at 10°-30°C.
• the MnO 2 is filtered off, the solvent is removed by distillation and the mixture is worked up in customary manner.
• the acetyl group is eliminated in the presence of acids.
• Acids used are, for example, hydrochloric acid, sulphuric acid, hydrobromic acid, phosphoric acid, methanesulphonic acid, benzenesulphonic acid or strongly acidic ion exchangers.
• the reaction is carried out in suitable diluents.
• suitable diluents for example alcohols such as methanol, ethanol and i-propanol, and ketones such as acetone.
• the reaction is carried out at temperatures between 0° and 150°C., preferably 50°-120°C., and at atmospheric pressure.
• nitropyridines of the formula III are new. Their preparation is described below in (5).
• Reductants used are preferably iron filings, or tin(II) chloride in the presence of an acid.
• Acids used are, for example, hydrohalic acids such as hydrochloric acid and hydrobromic acid, or glacial acetic acid. 0.3-10 moles of acid per mole of compound of the formula III are employed. However, the reduction can also be carried out in the acid as diluent.
• the reaction can also be carried out in the presence of other diluents.
• diluents are, for example, alcohols such as methanol, ethanol, butanol, acetic acid, water or mixtures of these diluents.
• the reductant is employed in excess. 6-15, preferably 6-9, reducing equivalents of reductants are employed per mole of the compound III.
• the reaction is carried out between 0° and 150°C., preferably 50°-120°C.
• Working up takes place by filtering the reaction mixture after completion of the reduction, rendering the filtrate alkaline, for example using aqueous sodium hydroxide solution, and extracting the compound of the formula II in a customary manner.
• Process (5) can be represented by the following equation: ##STR14##
• Process (5) is carried out by treating the compound of the formula IV with 2 to 15 moles, preferably 2 to 4 moles, of the inorganic acid chloride, if appropriate in a diluent.
• the reaction is carried out at temperatures of 20°C. to 150°C., and it is preferably carried out at atmospheric pressure.
• the reaction can take place in the presence of acid-binding agents.
• acid-binding agents Those which may be preferably mentioned are tertiary organic amines such as, for example, triethylamine, tripropylamine, tributylamine, N,N-dimethylaniline and pyridine.
• inert organic solvents can be used as diluents.
• these include aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene, methylene chloride, chloroform and chlorobenzene; ethers such as diethyl ether, tetrahydrofuran, dioxane, nitriles and esters.
• the reaction is preferably carried out without diluents.
• Process (7) can be represented by the following equation: ##STR15##
• 6-Ethyl-4-hydroxy-pyrid-2-one of the formula V is new. Its preparation is described below.
• the reaction is carried out in nitric acid or in a mixture of nitric acid and sulphuric acid as nitrating agent At least 1-5 moles of nitrating agent per mole of compound of the formula V are employed.
• the reaction is carried out between -10° and 150°C., preferably between 0° and 100°C. and also at atmospheric pressure.
• reaction mixture is diluted with water and the compound of the formula IV is filtered off.
• 6-Ethyl-4-hydroxy-3-carbalkoxy-pyridines of the formula VI are new.
• Compounds of the formula VI are preferred in which R 3 stands for methyl or ethyl.
• Decarboxylation to compounds of the formula V is carried out in the presence of aqueous bases such as alkali metal hydroxides or alkaline earth metal hydroxides. 2-10, preferably 2-5, moles of base per mole of compound of the formula VI are employed. The reaction is carried out between 20° and 200°C., preferably between 50° and 150°C.
• aqueous bases such as alkali metal hydroxides or alkaline earth metal hydroxides. 2-10, preferably 2-5, moles of base per mole of compound of the formula VI are employed.
• the reaction is carried out between 20° and 200°C., preferably between 50° and 150°C.
• the compounds of the formula VI can be prepared by reacting enamines of the formula VIII ##STR17## in which
• C 1-4 -alkyl preferably stands for methyl or ethyl, with malonates of the formula IX ##STR18## in which
• C 1-4 -alkyl preferably stands for methyl or ethyl, in the presence of bases.
• the compounds of the formula VIII and IX are employed in a molar ratio of about 1:1.
• Bases used are alkali metal alkoxides and alkaline earth metal alkoxides such as sodium methoxide or potassium t-butoxide.
• the bases are employed in a ratio of 1:3, preferably 1:1.5, per mole of malonate.
• Diluents used are alcohols such as methanol, ethanol, i-propanol, t-butanol and also inert organic solvents, in particular aliphatic and aromatic, optionally halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, moreover amides such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone and also dimethyl sulphoxide, tetramethylene sulphone
• 6-acetyl-3-amino-2,4-dihalogenopyridines of the formula I can be used in order to prepare pyridinethanolamines.
• Sulphuryl chloride is preferably employed as a halogenating agent in reaction step 10a.
• the reaction is carried out in the presence of diluents.
• diluents Those which may be mentioned are aliphatic, optionally halogenated hydrocarbons such as, for example, pentane, hexane, heptane, ligroin, cyclohexane, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, alcohols such as methanol and ethanol, esters such as methyl acetate or ethyl acetate and mixtures of these diluents.
• aliphatic, optionally halogenated hydrocarbons such as, for example, pentane, hexane, heptane, ligroin, cyclohexane, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, alcohols such as methanol and ethanol, esters such as methyl acetate or ethyl acetate and
• the reaction is carried out between -20° and +150° C., preferably between 0° and 70° C., and at atmospheric pressure.
• Reaction step 10b is preferably carried out using the reductants diborane or complex hydrides such as, for example, sodium borohydride or lithium borohydride.
• step 10c the following amines are preferably employed: ammonia, methylamine, i-propylamine, i-butyl-amine, sec. -butylamine, tert.-butylamine, cyclopentylamine, cyclohexylamine, 1-cyclohexylethylamine, benzyl-amine, 2-phenylethylamine and 2-phenyl-propylamine.
• Step 10 can be carried out with or without diluents.
• Diluents which may be mentioned are: in particular, aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene; furthermore ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane; furthermore nitriles, such as, for example, acetonitrile and propionitrile, benzonitrile, and glutaronitrile : moreover amides, such as, for example, dimethylformamide, dimethylacet
• Step 10c can be carried out in the presence of catalysts such as, for example, alkali halides, for example sodium bromide, potassium iodide, quaternary ammonium iodides or quaternary ammonium bromides.
• catalysts such as, for example, alkali halides, for example sodium bromide, potassium iodide, quaternary ammonium iodides or quaternary ammonium bromides.
• the reaction is carried out at temperatures of 25°-250°C., preferably 50°-150°C.
• the reaction is carried out at atmospheric pressure or under elevated pressure.
• the filtrate is rendered alkaline using sod hydroxide solution and extracted using dichloromethane. After evaporating, 20 g (95.5% of theory based on the purity of the starting material employed) of 3-amino2,4-dichloro-6-ethylpyridine remain.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pyridine Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=6349468

Family Applications (1)

Country Status (4)

Cited By (2)

Citations (4)

Family Cites Families (1)

• 1988
  • 1988-03-11 DE DE3808115A patent/DE3808115A1/de not_active Withdrawn
• 1989
  • 1989-03-01 EP EP19890103541 patent/EP0332030A3/de not_active Withdrawn
  • 1989-03-02 JP JP1048689A patent/JPH01268676A/ja active Pending
  • 1989-03-07 US US07/320,132 patent/US4939262A/en not_active Expired - Fee Related

Patent Citations (4)

Also Published As

Similar Documents

Legal Events